Knockdown of lamin B1 and the corresponding lamin B receptor led to changes in heterochromatin state and senescence induction in malignant melanoma

Changes in nuclear structures of cells are often related to several diseases including cancer. Dysfunction of the nuclear envelope could be associated with changes in nuclear activity, structural dynamics and cell signaling. The role of the nuclear lamina and related proteins in malignant melanoma is still unraveled. Therefore, understanding the biological role of the nuclear structure in melanoma might lead to the development of new therapy approaches. In this in vitro study we analysed the functional effects of dysregulated nuclear lamin B1 (LMNB1) and the nuclear envelope transmembrane protein Lamin B receptor (LBR), binding LMNB1. According to their cellular localization and function, these genes are involved in nuclear processes like chromatin organisation. However, their molecular role in influencing the chromatin state in melanoma is still completely unknown. Additionally, to our in vitro studies, RNA-sequencing and differential gene expression analysis were used to determine potential target molecules related to the functional role of LMNB1 and LBR. The gene expression analysis revealed the implication of molecules involved in important cellular processes driving ER stress leading to senescence and changes in chromatin state, which were also experimentally validated. We hypothesize that melanoma cells need both molecules independently to be prevented from senescence. Hence, a downregulation of both molecules in a lentiviral BRAFV600E expressing melanocytic senescence model as well as in etoposide treated melanoma cells indicates both as potential senescence marker in melanoma. Our findings suggest for the first time that LMNB1 and LBR influence senescence and affect nuclear processes like chromatin condensation and thus are functional relevant for melanoma progression.